Two highly significant and challenging health care problems converge in the comorbidity of chronic pain and smoking. Chronic pain affects ~116 million persons. Among those with chronic pain, the prevalence of smoking (~50%) is more than twice that in the general population (~21%). This association is alarming. Not only is smoking the leading preventable cause of mortality, but clinical studies clearly demonstrate that smoking exacerbates both the intensity and associated impairments of chronic pain. Moreover, smoking rates are positively correlated with pain severity and its resulting functional impairment. Clinical observations suggest that chronic pain and nicotine use are intertwined in a positive feedback loop. Individuals smoke to relieve their pain, smoking exacerbates the pain, and individuals in turn continue to smoke or smoke more in an effort to alleviate the pain. In addition, persistent pain may diminish the rewarding properties of nicotine. With the rapid acceptance of ?vaping? nicotine as a ?safer? alternative to smoking, the comorbidity of nicotine use and chronic pain will persist as a significant health care problem. Systematic studies of the mechanistic basis for the comorbidity of nicotine use and chronic pain are lacking in the preclinical literature. This explora- tory R21 proposal seeks to test the hypothesis that chronic exposure to nicotine enhances the somatosensory components of pain, exacerbates on-going pain and increases the averseness of noxious stimulation following peripheral injury. To do so, it will use a new method for chronic, intermittent administration of nicotine by inhalation that mimics the pharmacokinetics of nicotine in smokers. It will determine how prior intermittent exposure to nicotine alters the organism's response to peripheral nerve or inflammatory injury using a battery of tests that assess heat hyperalgesia, mechanical hypersensitivity, on-going pain and the aversiveness of noxious stimulation. These measures will be made in the period immediately before injury, shortly after injury (acute pain) and again two weeks later (chronification of pain). In a complementary aim, autoradiography will be used to quantitate ?4?2 and ?7 nicotinic acetylcholine receptors, and to determine how chronic nicotine, chronic pain and the combination of chronic nicotine and chronic alter these receptors. The dorsal horn, as well as cortical, midbrain, pontine, and medullary nuclei implicated in reward or in pain modulation will be surveyed. These studies will be conducted in male and female rats to investigate potential sex differences given that the prevalence of chronic pain is greater in women and women find nicotine more rewarding. Successful interventions against chronic pain in those who smoke or vape nicotine will require a much better understanding of the pharmacological and physiological bases for the feedforward relationship. Validation of a preclinical model of concomitant chronic pain and nicotine use is a necessary first step, and will provide foundational data to drive additional mechanistic studies. Insights gained from this work will also guide new approaches to abrogate the chronification of pain in other populations as well.